AB0521 IDENTIFICATION OF AN INTERFERON 5-GENE SIGNATURE SCORE AS A PHARMACODYNAMIC AND POTENTIAL PREDICTIVE BIOMARKER FOR DEUCRAVACITINIB TREATMENT IN A PHASE 2 TRIAL IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: C. Wu, Y. Hu, M. K. Crow, A. Saxena, C. Arriens, C. Hobar, A. Coles, I. M. Catlett
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Tyrosine kinase 2 (TYK2) mediates cytokine pathways (eg, Type I IFN) linked with systemic lupus erythematosus (SLE) pathogenesis. Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis <sup>[1,2]</sup>. Deucravacitinib was efficacious compared with placebo in a phase 2 SLE trial <sup>[3]</sup>. <h3>Objectives</h3> To develop a customized IFN 5-gene signature score, assess the pharmacodynamic effects of deucravacitinib on the IFN score, and evaluate the score's association with SLE disease activity and clinical response in the phase 2 trial. <h3>Methods</h3> Patients with active SLE were randomized equally to oral placebo or deucravacitinib (3 mg BID, 6 mg BID, or 12 mg QD). DxTerity chemical ligation-dependent probe amplification was used to measure 51 immune system-related genes from whole blood. IFN genes were selected based on distribution, correlations, hierarchical clustering, and consistency of k-means clusters. Serum proteins, blood cell subsets, and antibody profiles were measured by immunoassays and flow cytometry. SRI(4) and BICLA were measured at weeks 32 and 48. <h3>Results</h3> An IFN 5-gene (<i>MX1</i>, <i>HERC5</i>, <i>IFIT1</i>, <i>RSAD2</i>, and <i>EIF2AK2</i>) signature score was identified and used to classify patients into IFN-high or IFN-low subgroups (<b>Figure 1</b>). Higher baseline IFN score was associated with higher baseline SLEDAI and CLASI disease activity scores, higher levels of IFN activity biomarker (eg, IFNα, IFNλ, BAFF, CXCL10) and anti-dsDNA, and lower complement and lymphocyte counts. Baseline IFN score was not predictive of SRI(4) response. A higher baseline IFN score was associated with a significantly higher probability of BICLA response with deucravacitinib 3 mg BID relative to placebo (<i>P</i>=0.014). Deucravacitinib reduced the IFN score from weeks 4 through 44 by &gt;50%. <h3>Conclusion</h3> These data support the IFN 5-gene signature score as a biomarker to classify patients with SLE into IFN-high or IFN-low subgroups; however, clinical response by IFN score was inconsistently improved (<b>Table 1</b>). IFN-regulated gene expression performs well as a pharmacodynamic biomarker to confirm deucravacitinib mechanism of action and to aid in phase 3 dose selection. <h3>References</h3> [1]Armstrong A, et al. <i>J Am Acad Dermatol.</i> 2023;88(1):29-39. [2]Strober B, et al. <i>J Am Acad Dermatol.</i> 2023;88(1):40-51. [3]Morand E, et al. <i>Arthritis Rheumatol.</i> 2022; Nov 11 (Epub ahead of print). <h3>Acknowledgements</h3> This study was sponsored by Bristol Myers Squibb. <h3>Disclosure of Interests</h3> Chun Wu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Yanhua Hu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Mary K. Crow Consultant of: AMPEL BioSolutions, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Grant/research support from: Gilead Sciences, Amit Saxena Grant/research support from: AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Kezar Life Sciences, Cristina Arriens Speakers bureau: AstraZeneca, Aurinia, Bristol Myers Squibb, GlaxoSmithKline, Kezar, Grant/research support from: AstraZeneca, Bristol Myers Squibb, Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Adrian Coles Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Ian M. Catlett Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb.